RT Journal Article
SR Electronic
T1 Identification of novel disease relevant genetic modifiers affecting the SHH pathway in the developing brain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.03.366302
DO 10.1101/2020.11.03.366302
A1 Nora Mecklenburg
A1 Izabela Kowalczyk
A1 Franziska Witte
A1 Jessica Görne
A1 Alena Laier
A1 Hannes Gonschior
A1 Martin Lehmann
A1 Matthias Richter
A1 Anje Sporbert
A1 Bettina Purfürst
A1 Norbert Hübner
A1 Annette Hammes
YR 2020
UL http://biorxiv.org/content/early/2020/11/03/2020.11.03.366302.abstract
AB Pathogenic gene variants in humans affecting the sonic hedgehog (SHH) pathway lead to severe brain malformations with variable penetrance due to unknown genetic modifiers. To identify such modifiers, we established novel congenic mouse models. LRP2 deficient C57BL/6N mice suffer from heart outflow tract defects and holoprosencephaly caused by impaired SHH activity. These defects are fully rescued on FVB/N background indicating a strong influence of modifier genes. Applying comparative transcriptomics, we identified Pttg1 and Ulk4 as candidate modifiers upregulated in the rescue strain. Functional analyses showed that ULK4 and PTTG1, both microtubule-associated proteins, are new positive regulators of SHH signaling, rendering the pathway more resilient to disturbances. In addition, we characterized PTTG1 as a novel primary cilia component in the neuroepithelium. The identification of genes, that powerfully modulate the penetrance of genetic disturbances affecting the brain and heart, is likely relevant to understand variability in human congenital disorders.Competing Interest StatementThe authors have declared no competing interest.